Tibotec Files NNRTI Rilpivirine, Part Of Gilead's New Combo For HIV

Johnson & Johnson subsidiary Tibotec has submitted its once-daily non-nucleoside reverse transcriptase inhibitor TMC278 (rilpivirine) for treatment-naïve HIV patients for FDA approval, close on the heels of releasing pivotal data at the International AIDS Society meeting in Vienna.

The application covers use of the NNRTI with other antiretroviral agents in treatment-naïve adults with HIV, the Cork, Ireland-based company announced on July 26. In the coming months, regulatory submissions will follow in other countries.

Gilead is developing a combination pill that includes TMC278 with its own Truvada (emtricitabine/tenofovir). The triple combination is being positioned as a replacement for Gilead's standard-of-care treatment Atripla , a combination of Truvada with Bristol-Myers Squibb's NNRTI Sustiva (efavirenz), which loses patent protection in 2013.

The timing of the rilpivirine filing was in line with investors' expectations and paves the way for Gilead to file the TMC278/Truvada combination as soon as FDA accepts the submission, commented Baird analyst Thomas Russo. Tibotec confirmed that it is not seeking priority review, so a standard 10-month user fee clock can be expected.

Tibotec already markets the twice-daily NNRTI Intelence (etravirine), which was cleared for use in patients with resistance to other NNRTIs and antiretrovirals by FDA under accelerated approval in 2008 (¹ (Also see "J&J’s Intelence Approved For HIV Treatment In NNRTI-Resistant Patients" - Pink Sheet, 22 Jan, 2008.)). But the company notes that the two drugs target different patient populations, with no overlap. Tibotec does not plan to test TMC278 in treatment-experienced patients. In addition to Intelence, which was converted to a full approval in 2009, Tibotec also currently markets the protease inhibitor Prezista (darunavir) (² (Also see "Merck Pushes Discount Zocor; Health Plans Are Wary, But Pfizer Is Concerned" - Pink Sheet, 26 Jun, 2006.)).

The TMC278 application, for full approval, is supported by 48-week results from two pivotal Phase III double-blind randomized trials - ECHO and THRIVE - evaluating safety and efficacy in 1,368 treatment-naïve adults with HIV. The studies were almost identical aside from background therapy. The ECHO study compared rilpivirine against efavirenz, with Truvada as a background regimen in both groups. The THRIVE trial compared rilpivirine against efavirenz with investigator-selected background regimens of either Viiv's Epzicom (abacavir/lamivudine) or Truvada. Sixty percent chose Truvada.

A pooled analysis of ECHO and THRIVE results showing that rilpivirine successfully met the primary efficacy endpoint of non-inferiority to Sustiva in terms of effects on viral load was presented at the International AIDS Society meeting in July (³ (Also see "Gilead: Near-Term Drug Filings Planned, But HIV Pressure Persists" - Pink Sheet, 21 Jul, 2010.)).

Rilpivirine is expected to be differentiated from Sustiva based on a much better tolerability profile, particularly when it comes to psychiatric effects like dizziness and abnormal dreams. Results from the pivotal studies bear this out. Patients on TMC278 reported fewer adverse events leading to discontinuation (3.4 percent versus 7.6 percent for efavirenz). Grade 2 to 4 adverse event rates were lower for the TMC278 arm: 14.9 percent vs. 22.7 percent for psychiatric events, 17.1 percent vs. 37.8 percent for neurological and 3.1 percent vs. 13.6 percent for rash.

Two Trials Yield Mixed Outcomes

However, the test-drug patients overall also had a higher virologic failure rate (9 percent versus 4.8 percent for Sustiva) in the pooled analysis. The failure rate was higher due to the development of class resistance mutations (39 versus 15) and also to the development of resistance mutations to another class of drugs, NRTIs (42 versus 9). An association between failure rates and higher viral loads was observed.

Baird's Russo noted that data at 96 weeks should shed more light on the virological failure issue. In Phase II, the virologic failure rates for efavirenz and TMC278 converged after longer term data collection, because efavirenz was not as well-tolerated.

That might not sway clinicians, though. Bradley Hare, medical director of the UCSF Positive Health Program, commented that failure due to intolerability and failure due to treatment resistance are not equal. If a patient fails a drug due to side effects, he or she can be switched to another drug, whereas development of treatment resistance has the potential to cut treatment options in the future. Clinicians may be wary of prescribing for that reason, he said.

The potential for treatment resistance will be weighed against the advantages of having a once-daily, relatively well tolerated pill, he said. Pfizer's CCR5 co-receptor antagonist maraviroc ( Selzentry ) had compelling safety data but a mixed picture on efficacy, and the drug nevertheless won FDA approval, Hare pointed out (⁴ (Also see "FDA Expands Selzentry Indication, But Ties Use To Screening With "Highly Sensitive" Assay" - Pink Sheet, 25 Nov, 2009.)).

The lead investigator on ECHO and THRIVE, Cal Cohen of The Community Research Initiative of New England, agreed that Selzentry appeared to offer better tolerability with a modest trade-off in efficacy. But the drugs are different molecules and, in the case of Selzentry, only one pivotal trial supported the application. Thus the TMC278 package will offer a greater range of evidence.

The virologic failure results in the TMC278 are being studied further, Cohen said.

The finding may not be related to an intrinsic property of the drug, but rather to differences in the way certain patients took the drug or even to chance, he said in an interview. Interestingly, the difference in virologic failure rates between TMC278 and efavirenz were noted in the ECHO study but not the THRIVE trial, and reasons for the discrepancy are unclear, Cohen said. The difference was not correlated to difference in background regimens between the two trials, he added.

Tibotec is actively exploring the factors that could explain the difference in outcomes. It could be due to the way patients at some sites took the drug - TMC278 needs to be taken with food and its efficacy can be affected by proton pump inhibitors.

The goal now is to identify the factors that will yield the success rate observed in THRIVE, which will give clinicians confidence in prescribing the drug, Cohen said.

- Emily Hayes ( ⁵ [email protected] )